This invention relates to a method for treating severe tinnitus.
Tinnitus is the perception of ringing, hissing, or other sounds in the ears or head when no external sound is present. For some people, tinnitus is just a nuisance. For others, it is a life-altering condition. According to the American Tinnitus Association, over 50 million Americans experience tinnitus to some degree and of these, approximately 12 million people have tinnitus to a distressing degree.
Approximately 2 million Americans have tinnitus to the point where they are so seriously debilitated that they cannot function on a xe2x80x9cnormalxe2x80x9d day-to-day basis and some may commit suicide. Lewis, J. E., S. D. G. Stephens, et al. (1993). xe2x80x9cTinnitus and suicide.xe2x80x9d Clin Otolaryngol 19: 50-54. It is this severely affected population, which is only poorly managed with therapies available today, that may benefit from intrathecal pharmacotherapy proposed in the current investigation.
In terms of population percentages, approximately 17% of the general population, and 33% of the elderly population suffer from tinnitus. McFadden, D. (1982). Tinnitus: Facts, Theories, and Treatments. Washington D.C., National Academy Press; and Sataloff, J., R. T. Sataloff, et al. (1987). xe2x80x9cTinnitus and vertigo in healthy senior citizens without a history of noise exposure.xe2x80x9d Am J Otol 8(2): 87-89.
Axelsson and Ringdahl reported that approximately 2.5% of the tinnitus patients that they surveyed complained that tinnitus xe2x80x9cplagued me all day.xe2x80x9d Axelsson, A. and A. Ringdahl (1989). xe2x80x9cTinnitus-a study of its prevalence and characteristics.xe2x80x9d British Journal of Audiology 23: 53-62. In Western countries various investigators have reported 0.5% to 1.0% of the population are severely affected by tinnitus to the extent that it interferes with their normal working and leisure life. Coles, R. R. A., A. C.
Thompson, et al. (1992). xe2x80x9cIntra-tympanic injections in the treatment of tinnitus.xe2x80x9d Clin Otolaryngol 17(3): 240-242.
Despite the large medical impact of tinnitus, no widely accepted, effective treatment exists for the majority of cases of tinnitus. Dobie, R. A. (1999). xe2x80x9cA review of randomized clinical trials in tinnitus.xe2x80x9d The Laryngoscope 109: 1202-1211; Simpson, J. J. and W. E. Davies (1999). xe2x80x9cRecent advances in the pharmacological treatment of tinnitus.xe2x80x9d TiPS 20: 12-18.
In the vast majority of tinnitus cases an underlying cause is not apparent, and effective treatments (i.e., treatments which actually eliminate or reduce the sound) are not available. Most of the therapies that are presently available attempt to minimize the patients"" awareness of the tinnitus symptoms or reduce their emotional reaction to their condition.
Rational treatment for the small proportion of patients with a reversible cause for their tinnitus involves correcting the underlying condition. This may involve removing or reducing the dose of the pharmacologic mediator (e.g., aspirin, aminoglycoside) or correcting the mechanical defect in the peripheral auditory system (e.g., remove obstructions in external auditory canal, surgically correct middle ear problems, or surgically decompress microvascular compressions of the auditory nerve).
The most common method used to manage mild to moderate tinnitus is masking. In its simplest form, masking consists of self-exposure to background noise such as, radio, television, or recorded music. People with normal hearing and severe tinnitus can wear a small hearing-aid-like device that produces background (masking) noise in the affected ear. Patients with concomitant impaired hearing and tinnitus sometimes benefit (both their hearing and tinnitus) from use of a conventional hearing aid.
Limbic structures of the brain may be involved in the neural plastic changes associated with tinnitus. Supportive of this notion is the observation that the perceived amplitude of the tinnitus often does not correspond to the overall severity of the condition. For example, some patients with tinnitus of a relatively low volume are extremely disturbed, whereas others with high volume tinnitus are relatively unaffected by it. Lockwood, A. H., R. J. Salvi, et al. (1998). xe2x80x9cThe functional anatomy of gaze-evoked tinnitus: Evidence for limbic system links and neural plasticity.xe2x80x9d Neurology 50: 114-120.
Some researchers have used this observation to justify treatments based upon a habituation counseling strategy. Jastreboff, P. J., W. C. Gray, et al. (1996). xe2x80x9cNeurophysiological approach to tinnitus patients.xe2x80x9d Amer J Otol 17: 236-240. Habituation is a psychological technique that trains patients to ignore or minimize their emotional reaction to tinnitus. Habituation is traditionally defmed as the disappearance of reactions to sensory stimuli because of repetitive exposure and the lack of positive or negative reinforcement. A necessary condition for inducing habituation is to remove the association between tinnitus and the emotional state, i.e., to remove the activation of the limbic system by the tinnitus signal. The most popular version of this therapy, tinnitus retraining therapy, has been developed and popularized by Dr. Pawel Jastreboff. The process typically requires approximately 12 months of therapy. Treatments tend to be more successful for mild and moderate forms of tinnitus and for cases of shorter duration.
The drugs most commonly used to manage tinnitus are antidepressants (especially tricyclics) and anxiolytics (valium, alprazolam, buspirone), although they have limited efficacy. Anxiolytics and antidepressants affect the secondary psychological sequelae of tinnitus, rather than the perception of the noise itself. The neural plasticity associated with tinnitus may involve the formation of new neural connections between the auditory and limbic systems of the brain. Moller, A. R. (2001). xe2x80x9cSymptoms and signs caused by neural plasticity.xe2x80x9d Neurological Research 23: 565-572.
Although numerous other drugs have been tried, the majority of clinical trials have produced negative results. Dobie, R. A. (1999). xe2x80x9cA review of randomized clinical trials in tinnitus.xe2x80x9d The Laryngoscope 109: 1202-1211. Most agents have been administered orally, although several clinical trials attempting to directly administer agents into the ear have also failed to show efficacy. Coles, R. R. A., A. C. Thompson, et al. (1992). xe2x80x9cIntra-tympanic injections in the treatment of tinnitus.xe2x80x9d Clin Otolaryngol 17(3): 240-242.
Lidocaine
Intravenously (IV) administered lidocaine is the only drug that has demonstrated consistent, significant, and reproducible efficacy against tinnitus. den Hartigh, J., C. G. J. M. Hilders, et al. (1993). xe2x80x9cTinnitus suppression by intravenous lidocaine in relation to its plasma concentration.xe2x80x9d Clin Pharmaocol and Ther 54: 415-420. Unlike other commonly prescribed oral medications that tend to manage only the emotional symptoms associated with tinnitus, lidocaine actually reduces or eliminates the noise. Lidocaine ameliorates tinnitus in approximately 60-80% of sufferers, a result that has been replicated in numerous well-controlled clinical trials. Merchant, S. N. and M. V. Kirtane (1986). xe2x80x9cVestibular effects of intravenous lidocaine used in the treatment of tinnitus.xe2x80x9d J Laryngol Otol 100: 1249-1253. The efficacy of IV lidocaine is greater than the efficacy produced by auditory nerve transection (approximately 50%), suggestive of a central mechanism of lidocaine action. However, locally administered lidocaine (to the ear or cochlea) has been relatively ineffective. In addition, locally administered lidocaine to the ear has been associated with significant vestibular side effects such as vertigo and nausea. Ochi, K. and J. J. Eggermont (1996). xe2x80x9cEffects of salicylate on neural activity in cat primary auditory cortex.xe2x80x9d Hearing Research 95(1-2): 63-76; Podoshin, L., M. Fradis, et al. (1992). xe2x80x9cTreatment of tinnitus by intratympanic installation of lignocaine (lidocaine) 2 percent through ventilation tubes.xe2x80x9d J Laryngol Otol 106(7): 603-606.
Despite the efficacy of IV lidocaine, it unfortunately does not represent a clinically useful therapy. Tinnitus patients effectively treated with IV lidocaine in the short term, usually experience a return of their symptoms shortly after the medication has been stopped. Intravenous lidocaine (bolus administration) has a short duration of action (10-20 minutes) and is metabolized rapidly by the liver (terminal half life of 1.5 to 2 hours in humans). Lidocaine used in the treatment of cardiac arrhythmias is typically diluted with saline, and administered as a precisely-metered IV infusion. Unfortunately in tinnitus patients with healthy heart rhythms, IV lidocaine can induce potentially life-threatening cardiac arrhythmias. Intravenous lidocaine at effective doses also can cause nausea and dizziness. If administered orally, lidocaine is ineffective due to a major first pass effect.
Tinnitus is associated wi th abnormal spontaneous neural activity at multiple levels within the central auditory pathways. Gamma-amino-butyric acid (GABA) is the main inhibitory neurotransmitter of the mammalian CNS. An example of a GABAB-receptor agonist is baclofen, which mimics in part the effects of GABA.
Several studies have correlated age-related changes in the concentrations of GABA and GABAB-binding sites in the Inferior Colliculus (xe2x80x9cICxe2x80x9d), the major auditory midbrain structure. Caspary, D. M., J. C. Milbrandt, et al. (1995). xe2x80x9cCentral auditory aging: GABA changes in the inferior colliculus.xe2x80x9d Experimental Gerontology 30(3/4): 349-360; Raza, A., J. C. Milbrandt, et al. (1994). xe2x80x9cAge-related changes in brainstem auditory neurotransmitters: measures of GABA and acetylcholine function.xe2x80x9d Hear Res 77(1-2): 221-230. Age-related decreases in the enzyme responsible for GABA synthesis (glutamic acid decarboxylase) have been reported in the IC of both rats and humans. McGeer, E. G. and P. L. McGeer (1975). Age changes in the human for some enzymes associated with metabolism of the catecholamines, GABA and acetycholine. Neurobioloby of Aging. J. Ordy, Brizzee KR. N.Y., Plenum Press: 287-305; Raza, A., J. C. Milbrandt, et al. (1994). xe2x80x9cAge-related changes in brainstem auditory neurotransmitters: measures of GABA and acetylcholine function.xe2x80x9d Hear Res 77(1-2): 221-230. In rats, age-related decreases in the levels of GABA and the number of GABAB-binding sites within the IC have also been reported. Araki, T., H. Kato, et al. (1993). xe2x80x9cSelective changes of neurotransmitter receptors in middle-aged gerbil brain.xe2x80x9d Neurochem Int 23(6): 541-548; Milbrandt, J. C., R. L. Albin, et al. (1994). xe2x80x9cAge-related decrease in GABAB receptor binding in the fischer 344 rat inferior colliculus.xe2x80x9d Neurobiol Aging 15(6): 699-703. These biochemical findings may explain why tinnitus is more prevalent among the elderly.
In addition to age-related biochemical changes, the inferior colliculus also shows changes in function (increased spontaneous activity) in response to noise exposure or injury to the peripheral auditory system, results commonly associated with tinnitus in humans. Moller, A. R., M. B. Moller, et al. (1992). xe2x80x9cSome forms of tinnitus may involve the extralemniscal auditory pathway.xe2x80x9d Laryngoscope 102(10): 1165-1171. In rats, IV baclofen inhibited noise-induced electrical potentials recorded directly from IC neurons. Szcepaniak, W. S. and A. R. Moller (1995). xe2x80x9cEffects L-baclofen and D-baclofen on the auditory system: a study of click-evoked potentials from the inferior colliculus in the rat.xe2x80x9d Ann Otol Rhinol Laryngol 104(5): 399-404; Szcepaniak, W. S. and A. R. Moller (1996). xe2x80x9cEffects of (xe2x88x92) baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: Possible therapeutic implications for pharmacological management of tinnitus and hyperacusis.xe2x80x9d Hear Res 97: 46-53. An additional observation suggestive of the inhibitory role of GABA in the normal auditory system comes from clinical reports of auditory hallucinations that are sometimes experienced with baclofen withdrawal in humans. Lees, A. J., C. R. Clarke, et al. (1977). xe2x80x9cHallucinations after withdrawal of baclofen.xe2x80x9d Lancet 8016: 858.
Additional evidence that may implicate GABA in the pathophysiology of tinnitus are: 1) Benzodiazepines are often used with moderate efficacy to treat tinnitus. As sedatives, they may reduce the stress associated with tinnitus. However, benzodiazepine-mediated modulation of GABAA receptors may also be involved. 2) Anecdotal reports describe the efficacy of gabapentin in tinnitus patients. Zapp, J. J. (2001). xe2x80x9cGabapentin for the treatment of tinnitus: A case report.xe2x80x9d ENT-Ear, Nose and Throat Journal: 114-116. Although the precise molecular mechanisms of gabapentin remain elusive, it is generally believed that gabapentin augments central GABA functions either by promoting its release and/or inhibiting its degradation. Kuzniecky, R., S. Ho, et al. (2002). xe2x80x9cModulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults.xe2x80x9d Neurology 58: 368-372; Petroff, O. A., F. Hyder, et al. (2000). xe2x80x9cEffects of gabapentin on brain GABA, homocamosine, and pyrrolidinone in epilepsy patients.xe2x80x9d Epilepsia 41(6): 675-680.
In light of the above preclinical data, a single placebo controlled human clinical trial was conducted to evaluate the efficacy of oral baclofen (xe2x89xa660 mg/day) to treat tinnitus. Westerberg, B. D., J. B. Roberson, et al. (1996). xe2x80x9cA double-blind placeb-controlled trial of baclofen in the treatment of tinnitus.xe2x80x9d Am J Otolaryngol 17: 896-903. The authors conducted a randomized, double-blinded study after anecdotal reports described patients who experienced beneficial subjective reduction in tinnitus while taking oral baclofen. The clinical trial used oral baclofen, up to 60 mg/day, in patients with chronic tinnitus. Not all of the patients had severe tinnitus, and for some, tinnitus was not their primary complaint. After a 3-week course of escalating doses (20 mg/dayxc3x971 week; then 40 mg/dayxc3x971 week; then 60 mg/day xc3x971 week) subjects were retested using the Tinnitus Handicap Inventory, loudness and pitch matching, and maskability of tinnitus using white noise. Subjective improvement in tinnitus occurred in only 9.7% of baclofen-treated patients as opposed to 3.4% in placebo-treated patients. This outcome was not statistically significant. Oral baclofen therapy was associated with significant side effects that included sedation, confusion, dizziness, GI upset, and weakness, the combination of which caused 25% of the enrolled patients to drop out of the trial.
These side effects are also associated with oral baclofen used to treat spasticity but are typically not a problem when baclofen is administered intrathecally to treat spasiticity. Coffey, R. J., D. Cahill, et al. (1993). xe2x80x9cIntrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multcenter study.xe2x80x9d J Neurosurg 78: 226-232; Meythaler, J. M., S. Guin-Renfroe, et al. (2001). xe2x80x9cContinuously infused intrathecal baclofen over 12 months for spastic hypertonia in adolescents and adults with cerebral palsy.xe2x80x9d Arch Phys Med Rehabil 82: 155-161; Penn, R. D., S. M. Savoy, et al. (1989). xe2x80x9cIntrathecal baclofen for severe spinal spasticity.xe2x80x9d New England Journal of Medicine 320: 1571-1521.
U.S. Pat. No. 5,676,655 discloses a method for implanting a neural prosthetic drug delivery apparatus into a target zone of a patient""s brain for reducing or eliminating the effects of tinnitus. The apparatus includes a catheter that is inserted into the patient""s auditory cortex or thalamus. The catheter microinfuses drugs that suppress or eliminate abnormal neural activity into geometrically separate locations of the patient""s cortex or thalamus, thereby reducing or eliminating the effects of tinnitus. The patent, however, deals with drug delivery directly into brain tissue or into specific anatomical structures, i.e. intraparenchymal drug delivery. There are a number of disadvantages to intraparenchymal drug delivery to treat severe tinnitus. For example, intraparenchymal drug delivery is relatively invasive and requires a highly trained neurosurgeon to implant the catheter into the brain tissue or specific anatomical structure.
One or more of the above-mentioned deficiencies in the art are satisfied by the method of the present invention of intrathecal drug delivery for the treatment of severe tinnitus. One embodiment of the invention involves the use of one or more therapeutic agents intrathecally to treat tinnitus. For example, a catheter is implanted into a patient, the catheter having a proximal end and a distal end. The distal end of the catheter is adapted to infuse at least one therapeutic agent intrathecally into a patient""s cerebrospinal fluid. The therapeutic agent or agents may comprise a local anesthetic such as lidocaine or bupivacaine, a GABA agonist such as baclofen or muscimol, or a serotonin agonist such as sumatriptan.
In one embodiment of the invention, the proximal end of the catheter is coupled to an implantable pump and the distal end of the catheter is inserted into the subarachnoid space of a patient""s spinal column. The implantable pump is operated to deliver at least one therapeutic agent through the distal end and directly into the cerebrospinal fluid contained in the subarachnoid space of the patient""s spinal column. The therapeutic agent or agents may comprise a local anesthetic such as lidocaine or bupivacaine, a GABA agonist such as baclofen or muscimol, or a serotonin agonist such as sumatriptan.